Safety of Daily Co-Trimoxazole in Pregnancy in an Area of Changing Malaria Epidemiology: A Phase 3b Randomized Controlled Clinical Trial

Abstract

IntroductionAntibiotic therapy during pregnancy may be beneficial and impacts positively on the reduction of adverse pregnancy outcomes. No studies have been done so far on the effects of daily Co-trimoxazole (CTX) prophylaxis on birth outcomes. A phase 3b randomized trial was conducted to establish that daily CTX in pregnancy is not inferior to SP intermittent preventive treatment (IPT) in reducing placental malaria; preventing peripheral parasitaemia; preventing perinatal mortality and also improving birth weight. To establish its safety on the offspring by measuring the gestational age and birth weight at delivery, and compare the safety and efficacy profile of CTX to that of SP.MethodsPregnant women (HIV infected and uninfected) attending antenatal clinic were randomized to receive either daily CTX or sulfadoxine-pyrimethamine as per routine IPT. Safety was assessed using standard and pregnancy specific measurements. Women were followed up monthly until delivery and then with their offspring up to six weeks after delivery.ResultsData from 346 pregnant women (CTX = 190; SP = 156) and 311 newborns (CTX = 166 and SP = 145) showed that preterm deliveries (CTX 3.6%; SP 3.0%); still births (CTX 3.0%; SP 2.1%), neonatal deaths (CTX 0%; SP 1.4%), and spontaneous abortions (CTX 0.6%; SP 0%) were similar between study arms. The low birth weight rates were 9% for CTX and 13% for SP. There were no birth defects reported. Both drug exposure groups had full term deliveries with similar birth weights (mean of 3.1 Kg). The incidence and severity of AEs in the two groups were comparable.ConclusionExposure to daily CTX in pregnancy may not be associated with particular safety risks in terms of birth outcomes such as preterm deliveries, still births, neonatal deaths and spontaneous abortions compared to SP. However, more data are required on CTX use in pregnant women both among HIV infected and un-infected individuals.Trial RegistrationClinicaltrials.gov NCT00711906.

Lack of effect of intermittent preventive treatment for malaria in pregnancy and intense drug resistance in western Uganda

“…This accords with findings from Malawi [ 34 ]. A slight superiority of daily cotrimoxazole over IPTp with SP in HIV-infected pregnant women was also observed in Togo [ 35 ] whereas the regimens had similar effects in Uganda [ 36 ] and Zambia [ 37 ]. Data of the present study, although comprising small numbers only, support the policy of using daily cotrimoxazole for malaria prevention in HIV-infected pregnant women instead of SP-IPTp.…”

Antimalarial drugs for preventing malaria during pregnancy and the risk of low birth weight: a systematic review and meta-analysis of randomized and quasi-randomized trials

“…No significant differences in the rate of adverse events or foetal loss were found in the remaining studies [ 17 , 18 , 32 – 38 , 41 – 45 , 47 – 53 ]. Ten trials (40 %) reported using intention-to-treat analysis [ 17 , 18 , 32 , 33 , 41 , 43 , 44 , 47 , 49 , 53 ]; two trials (8 %) carried out a modified intention-to-treat analysis [ 16 , 40 ]; and the remaining 13 studies (52 %) used a per-protocol analysis [ 34 – 39 , 42 , 45 , 46 , 48 , 50 – 52 ]. A summary of included studies evaluating the use of antimalarial drugs for preventing malaria during pregnancy and the risk of LBW is shown in Additional file 3 : Table S1.…”

“…Of the 25 studies included, only four studies (16 %) were considered as having a low risk of bias [ 16 , 37 , 49 , 53 ] and 17 studies (68 %) were judged as presenting a high risk of bias [ 17 , 18 , 32 – 36 , 38 , 43 – 48 , 50 – 52 ]. The risk of bias was unclear in the remaining four studies (16 %) [ 39 – 42 ].…”

Antibiotics in malaria therapy: which antibiotics except tetracyclines and macrolides may be used against malaria?

“…Additionally, co-trimoxazole could also be a good alternative in malaria prophylaxis for different target groups, including children and adults, HIV positive or negative patients and pregnant women [12–15]. Daily use of co-trimoxazole during pregnancy had similar effects as intermittent preventive treatment (IPT) in terms of preterm deliveries, stillbirths, neonatal deaths, spontaneous abortions or birth weights [14]. Co-trimoxazole is effective (above 90%) for uncomplicated malaria treatment in children in areas of high endemicity [12, 16–18].…”